EP0007689B1 - Herstellung von Natrium-Cephamandolderivaten - Google Patents

Herstellung von Natrium-Cephamandolderivaten Download PDF

Info

Publication number
EP0007689B1
EP0007689B1 EP79301030A EP79301030A EP0007689B1 EP 0007689 B1 EP0007689 B1 EP 0007689B1 EP 79301030 A EP79301030 A EP 79301030A EP 79301030 A EP79301030 A EP 79301030A EP 0007689 B1 EP0007689 B1 EP 0007689B1
Authority
EP
European Patent Office
Prior art keywords
sodium
suspension
cefamandole
crystalline
formylcefamandole
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Expired
Application number
EP79301030A
Other languages
English (en)
French (fr)
Other versions
EP0007689A1 (de
Inventor
Kuo Shang Yang
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Eli Lilly and Co
Original Assignee
Eli Lilly and Co
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Eli Lilly and Co filed Critical Eli Lilly and Co
Publication of EP0007689A1 publication Critical patent/EP0007689A1/de
Application granted granted Critical
Publication of EP0007689B1 publication Critical patent/EP0007689B1/de
Expired legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D501/00—Heterocyclic compounds containing 5-thia-1-azabicyclo [4.2.0] octane ring systems, i.e. compounds containing a ring system of the formula:, e.g. cephalosporins; Such ring systems being further condensed, e.g. 2,3-condensed with an oxygen-, nitrogen- or sulfur-containing hetero ring
    • C07D501/14—Compounds having a nitrogen atom directly attached in position 7
    • C07D501/16—Compounds having a nitrogen atom directly attached in position 7 with a double bond between positions 2 and 3
    • C07D501/20—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids
    • C07D501/24—7-Acylaminocephalosporanic or substituted 7-acylaminocephalosporanic acids in which the acyl radicals are derived from carboxylic acids with hydrocarbon radicals, substituted by hetero atoms or hetero rings, attached in position 3
    • C07D501/36—Methylene radicals, substituted by sulfur atoms

Definitions

  • This invention relates to a novel process for preparing a crystalline cephalosporin derivative.
  • Cefamandole has the chemical name 7 - (D - ⁇ - hydroxy - ⁇ - phenylacetamido) - 3 - (1 - methyl - 1 H - tetrazol - 5 - ylthiomethyl) - 3 - cephem - 4 - carboxylic acid or, alternatively, 7 - D - mandelamido - 3 - (1 - methyl - 1H - tetrazol - 5 - ylthiomethyl) - 3 - cephem - 4 - carboxylic acid.
  • U.S. Patent 3,928,592 disclose the sodium salt of the formate ester of cefamandole, known as 0-formylcefamandole, as a useful pro-drug of cefamandole and describe pharmaceutical formulations useful for parenteral administration.
  • O-Formylcefamandole is described as a stable, crystalline compound which, in contrast with cefamandole itself, is readily purified.
  • the invention provides a process for preparing the crystalline methanolate form of sodium cefamandole.
  • it relates to a process for preparing the crystalline methanolate form of sodium cefamandole which comprises the treatment of a methanolic suspension of sodium 0-formylcefamandole with a concentrated methanolic solution of sodium hydroxide to provide a suspension of crystalline sodium cefamandole methanolate.
  • a suspension of sodium O-formylcefamandole in methyl alcohol is mixed with a concentrated solution of sodium hydroxide in methyl alcohol to form a suspension of the crystalline methanolate form of sodium cefamandole.
  • the process is illustrated by the following reaction scheme.
  • the process involves the hydrolysis of the formate ester of O-formylcefamandole sodium under basic conditions to cefamandole sodium.
  • the sodium cefamandole is obtained in crystalline form as the methanolate. This crystalline form is described in U.S. Patent No. 4,054,738.
  • a suspension is formed of substantially pure crystalline sodium 0-formylcefamandole in methyl alcohol, the suspension containing between 1.5 per cent and 3 per cent water by volume and the suspension is mixed with a concentrated solution of sodium hydroxide in methyl alcohol.
  • the suspension is preferably agitated vigorously by rapid stirring or shaking during the addition of the sodium hydroxide solution.
  • the crystalline sodium cefamandole methanolate forms in the suspension and after addition of the base is complete, the crystals are preferably harvested without delay to prevent decomposition in the basic mother liquor.
  • the suspension of sodium 0- formylcefamandole in methyl alcohol used in the process contains about one gram of sodium O-formylcefamandole in a volume of methylalcohol of between 2.5 ml. and 3.5 ml. As noted above, between 1.5 percent and 3 percent by volume of water is included in the suspension. The amount of water is critical since it is essential in the process that the sodium cefamandole methanolate produced be substantially insoluble in the basic reaction mixture. Excess water in the suspension will promote solubility of the hydrolysis product which in the basic medium will undergo decomposition with an accompanying decrease in yield.
  • the concentrated solution of sodium hydroxide in methyl alcohol is preferably added slowly to the suspension of sodium 0- formylcefamandole with vigorous agitation.
  • Preferably sufficient concentrated solution of sodium hydroxide is added to adjust the pH of the suspension to between 8 and 10.
  • the pH of the suspension is conveniently measured indirectly by removing an aliquot and determining the pH of the water diluted aliquot with a pH meter.
  • the desired basicity of the suspension is achieved by adding about 1 ml. of a concentrated methanolic sodium hydroxide solution per gram of sodium 0- formylcefamandole in suspension.
  • a concentrated methanol solution of sodium hydroxide contains about 12 mg./ml.
  • the amount of sodium hydroxide added is critical in the process since an excess will cause decomposition associated with ⁇ -lactam scission as well as with other routes of decomposition. Too low a concentration of sodium hydroxide will not achieve the basicity at which the hydrolysis of the formate ester proceeds at a practical rate.
  • the process is carried out at a temperature between 20°C. and 30°C. and conveniently at about 25°C.
  • the sodium O-formylcefamandole used in the process is substantially pure. Substantially pure refers to a purity above about 95%.
  • the O-formylcefamandole sodium salt is sparingly soluble in methyl alcohol containing the low percentage by volume of water employed in the present process.
  • the solubility of various crystalline forms of sodium 0- formylcefamandole for example, the a, f3 and y forms described by U.S. Patent No. 4,006,138 can differ in their solubilities, they are all sparingly soluble in methyl alcohol. It appears, however, that the hydrolysis of the formate ester occurs with the small amount of ester which is in solution rather than at the surface of the suspended crystals. The latter site of hydrolysis is, however, not ruled out.
  • the crystalline suspension of sodium 0- formylcefamandole is converted to a crystalline suspension of sodium cefamandole methanolate without a complete solution occurring.
  • the suspension is preferably vigorously stirred for 15 to 30 minutes during which time the hydrolysis is completed and crystals of sodium cefamandole methanolate have formed.
  • the crystals are preferably harvested promptly to avoid decomposition in the basic medium.
  • the crystals can be harvested by conventional methods such as filtration, centrifugation, etc. After separation from the mother liquor the crystals can be washed with methanol and ether and then dried. Yields of sodium cefamandole methanolate of between 65 and 70% are generally obtained in the process.
  • the sodium cefamandole methanolate obtained in the process can be converted to the anhydrate crystalline form for pharmaceutical use by removal of the methanol of crystallization, for example as described in U.S. Patent No. 4,054,738.

Landscapes

  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Cephalosporin Compounds (AREA)

Claims (4)

1. Verfahren zur Herstellung des kristallinen Methanolats von Natriumcephamandol, dadurch gekennzeichnet, daß man bei einer Temperatur zwischen 20 und 30°C eine Suspension von Natrium-O-formylcephamandol in Methylalkohol, die ein Verhältnis von etwa 1 g Natrium-O-formylcephamandol auf 2,5 bis 3,5 ml Methylalkohol aufweist und 1,5 bis 3 Volumenprozent Wasser enthält, mit einer konzentrierten Lösung von Natriumhydroxid in Methylalkohol in einer Menge vermischt, die etwa 1 ml dieser konzentrierten Lösung auf 1 g Natrium-O-formylcephemandoi in der Suspension entspricht.
2. Verfahren nach Anspruch 1, dadurch gekennzeichnet, daß man das erhaltene kristalline Methanolat von Natriumcephamandol von der Suspension sbtrennt.
3. Verfahren nach Anspruch 1 oder 2, dadurch gekennzeichnet, daß man vom erhaltenen kristallinen Methanolat von Natriumcephamandol das Kristallmethanol unter Bildung von Natriumcephamanodolanhydrat entfernt.
4. Verfahren zur Herstellung von Natriumcephamandolanhydrat, dadurch gekennzeichnet, daß man das Kristallmethanol von dem nach dem Verfahren gemäß Anspruch 1 oder 2 erhaltenen kristallinen Methanolat von Natriumcephamandol entfernt.
EP79301030A 1978-06-05 1979-06-01 Herstellung von Natrium-Cephamandolderivaten Expired EP0007689B1 (de)

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US912613 1978-06-05
US05/912,613 US4168376A (en) 1978-06-05 1978-06-05 Process for crystalline sodium cefamandole

Publications (2)

Publication Number Publication Date
EP0007689A1 EP0007689A1 (de) 1980-02-06
EP0007689B1 true EP0007689B1 (de) 1982-08-04

Family

ID=25432187

Family Applications (1)

Application Number Title Priority Date Filing Date
EP79301030A Expired EP0007689B1 (de) 1978-06-05 1979-06-01 Herstellung von Natrium-Cephamandolderivaten

Country Status (30)

Country Link
US (1) US4168376A (de)
EP (1) EP0007689B1 (de)
JP (1) JPS54163591A (de)
AR (1) AR221240A1 (de)
AT (1) AT364462B (de)
AU (1) AU525538B2 (de)
BE (1) BE876532A (de)
BG (1) BG32858A3 (de)
CA (1) CA1122974A (de)
CH (1) CH639098A5 (de)
CS (1) CS207792B2 (de)
DD (1) DD144169A5 (de)
DE (1) DE2963471D1 (de)
DK (1) DK157759C (de)
EG (1) EG14096A (de)
ES (1) ES481295A1 (de)
FI (1) FI67223C (de)
FR (1) FR2428043A1 (de)
GB (1) GB2023588B (de)
GR (1) GR73835B (de)
HU (1) HU180455B (de)
IE (1) IE48572B1 (de)
IL (1) IL57396A (de)
LU (1) LU81347A1 (de)
NZ (1) NZ190548A (de)
PH (1) PH13643A (de)
PL (1) PL116636B1 (de)
PT (1) PT69679A (de)
RO (1) RO77194A (de)
ZA (1) ZA792753B (de)

Families Citing this family (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JPS57138959A (en) * 1981-02-23 1982-08-27 Fuji Xerox Co Ltd Holding mechanism of electrostatic recording head
EP0432297A1 (de) * 1989-12-13 1991-06-19 Technologitschen Kombinat Sa Promischlena Mikrobiologia Verfahren zur Herstellung des Natriumsalzes von O-formylcefamandol
US5550231A (en) * 1993-06-15 1996-08-27 Eli Lilly And Company Loracarbef hydrochloride C1-C3 alcohol solvates and uses thereof
CN104530086B (zh) * 2014-12-16 2015-12-09 天津大学 头孢孟多酯钠化合物的新晶型及其结晶制备方法

Family Cites Families (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3641021A (en) * 1969-04-18 1972-02-08 Lilly Co Eli 3 7-(ring-substituted) cephalosporin compounds
US4006138A (en) * 1975-04-11 1977-02-01 Eli Lilly And Company Crystalline form of sodium O-formylcefamandole
US4054738A (en) * 1975-12-22 1977-10-18 Eli Lilly And Company Sodium cefamandole crystalline forms
JPS5283574A (en) * 1976-01-01 1977-07-12 Lilly Co Eli Sephamandol salt crystal containing dioxane

Also Published As

Publication number Publication date
BE876532A (fr) 1979-11-26
PL116636B1 (en) 1981-06-30
DD144169A5 (de) 1980-10-01
EG14096A (en) 1983-03-31
GB2023588A (en) 1980-01-03
PH13643A (en) 1980-08-18
LU81347A1 (fr) 1979-09-11
FI67223B (fi) 1984-10-31
JPS54163591A (en) 1979-12-26
FR2428043B1 (de) 1983-03-25
EP0007689A1 (de) 1980-02-06
CS207792B2 (en) 1981-08-31
FI791646A (fi) 1979-12-06
AT364462B (de) 1981-10-27
AU4736479A (en) 1979-12-13
ATA401479A (de) 1981-03-15
DK157759C (da) 1990-07-09
IL57396A0 (en) 1979-09-30
IE48572B1 (en) 1985-03-06
CA1122974A (en) 1982-05-04
AU525538B2 (en) 1982-11-11
PL216089A1 (de) 1980-03-24
IL57396A (en) 1981-12-31
FR2428043A1 (fr) 1980-01-04
FI67223C (fi) 1985-02-11
HU180455B (en) 1983-03-28
ZA792753B (en) 1981-01-28
DE2963471D1 (en) 1982-09-30
GR73835B (de) 1984-05-04
NZ190548A (en) 1981-05-29
DK157759B (da) 1990-02-12
GB2023588B (en) 1982-12-22
IE791060L (en) 1979-12-05
RO77194A (ro) 1981-06-22
DK231979A (da) 1979-12-06
CH639098A5 (fr) 1983-10-31
AR221240A1 (es) 1981-01-15
BG32858A3 (en) 1982-10-15
US4168376A (en) 1979-09-18
ES481295A1 (es) 1980-08-16
PT69679A (en) 1979-06-01

Similar Documents

Publication Publication Date Title
JP3421354B2 (ja) 結晶性セフジニルアミン塩
RU2081121C1 (ru) Способ получения клавулановой кислоты или ее фармацевтически приемлемых солей или эфиров, соль клавулановой кислоты с амином
SU1508959A3 (ru) Способ получени производных карбапенема
KR910000420B1 (ko) 결정성 세펨-산 부가염의 제조방법
EP0647229B1 (de) Diaminsalze von clavulansäure
US4456753A (en) Process for the manufacture of highly crystalline sodium cefoperazone
EP0157538A2 (de) Kristallinische Ceftazidime-Salze
EP0007689B1 (de) Herstellung von Natrium-Cephamandolderivaten
CA2126401A1 (en) Bicyclic beta-lactam/paraben complexes
US20020193587A1 (en) Penicillin crystal and process for producing the same
CA1080696A (en) Sodium cefamandole crystalline forms
US20010044533A1 (en) Purification process
US4219641A (en) Process for preparing erythromycin succinate
EP0101170B1 (de) Verfahren zur Herstellung von Cefoperazon-Natrium
US3947414A (en) Cefamandole derivatives
SU925251A3 (ru) Способ получени кристаллической формы D-конфигурации полуторной натриевой соли 7 @ -/ @ -карбокси- @ -(п-оксифенил) ацетамидо/-7 @ -метокси-3-(1-метилтетразол-5-ил)-тиометил-1-оксадетиа-3-цефем-4-карбоновой кислоты
US3812188A (en) Purification of 7-chlorotetracycline
US2698323A (en) Preparation of alkali metal salts of penicillin
IE47441B1 (en) Process for preparing pure cefamandole from alkali metal and ammonium salts thereof
JPH06104670B2 (ja) 化学化合物の新規製法
JPH085898B2 (ja) セフォラニド誘導体
JPS63115886A (ja) 結晶性セフアロスポリン化合物
DK143031B (da) Fremgangsmaade til fremstilling af 7-aminocephalosporansyre
KR19980702445A (ko) 클라불란 산 염류

Legal Events

Date Code Title Description
PUAI Public reference made under article 153(3) epc to a published international application that has entered the european phase

Free format text: ORIGINAL CODE: 0009012

AK Designated contracting states

Designated state(s): DE GB IT NL SE

17P Request for examination filed
ITF It: translation for a ep patent filed

Owner name: MODIANO & ASSOCIATI S.R.L.

GRAA (expected) grant

Free format text: ORIGINAL CODE: 0009210

AK Designated contracting states

Designated state(s): DE GB IT NL SE

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: FR

Payment date: 19820916

Year of fee payment: 15

REF Corresponds to:

Ref document number: 2963471

Country of ref document: DE

Date of ref document: 19820930

ITTA It: last paid annual fee
PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: DE

Payment date: 19900330

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: GB

Payment date: 19900331

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: SE

Payment date: 19900420

Year of fee payment: 12

PGFP Annual fee paid to national office [announced via postgrant information from national office to epo]

Ref country code: NL

Payment date: 19900630

Year of fee payment: 12

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: GB

Effective date: 19910601

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: SE

Effective date: 19910602

PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: NL

Effective date: 19920101

GBPC Gb: european patent ceased through non-payment of renewal fee
NLV4 Nl: lapsed or anulled due to non-payment of the annual fee
PG25 Lapsed in a contracting state [announced via postgrant information from national office to epo]

Ref country code: DE

Effective date: 19920401

EUG Se: european patent has lapsed

Ref document number: 79301030.7

Effective date: 19920109

PLBE No opposition filed within time limit

Free format text: ORIGINAL CODE: 0009261

STAA Information on the status of an ep patent application or granted ep patent

Free format text: STATUS: NO OPPOSITION FILED WITHIN TIME LIMIT